Optimization and feedback control of HIFU power deposition through the analysis of detected signal characteristics

ABSTRACT

A system and method for adjusting or selecting the treatment parameters for HIFU signals to treat a target treatment site, and/or to aid in visualizing the likely degree and location of HIFU effects on patient tissue. The system transmits one or more test signals into patient tissue and receives signals created in response to the test signals. The signals are analyzed to determine a response curve of how a characteristic of the signal varies with the one or more test signals. The response curve of the detected signals is used to select a treatment parameter.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 12/187,318, filed Aug. 6, 2008, and also claims the benefit ofU.S. Patent Application No. 61/180,187, filed May 21, 2009, both ofwhich are expressly incorporated herein by reference.

BACKGROUND

As an alternative to more invasive types of surgical procedures, manyphysicians are employing the use of High Intensity Focused Ultrasound(HIFU) as a technique to therapeutically treat internal body tissues.With HIFU, an ultrasound signal of sufficient power (pressure andparticle velocity) and time is focused on a target volume of tissue inorder to change a state of the tissue by heating and/or by cavitation.

To be effective in treating tissue, the delivered energy of the HIFUsignal must be sufficient to cause the desired physical effect.Additionally, the energy must not be so great or uncontrolled as tocause unintended collateral damage to healthy tissues surrounding thetarget volume. The non-homogenous nature of tissue(s) in the bodycreates variations in attenuation, propagation velocity, and acousticimpedance that modify the expected acoustic wave propagation anddeposition of HIFU energy delivered to a target tissue volume whencompared to homogeneous material. The technology disclosed herein is amethod and apparatus for dynamically controlling and/or selectingparameters that affect the energy of a HIFU signal and/or the locationwhere the energy is directed so that the desired physical effect intissue is obtained and collateral damage to surrounding tissue isminimized.

SUMMARY

As indicated above, the technology disclosed herein is a method andapparatus for selecting and/or controlling one or more treatmentparameters such as the energy of a HIFU signal delivered by a transducerto a desired location in a patient. The one or more treatment parametersare selected or controlled based on an analysis of harmonic distortionor other changes in a detected signal characteristic that occur as aresult of a high amplitude pressure waveform traveling through tissue.

To select a treatment parameter of a HIFU signal that will be used totreat a target tissue site, one or more test signals are delivered tothe tissue. Each test signal is a continuous wave (CW) or pulsed modeultrasound signal that is focused on a target volume in the patient.Signals created by the test signals are received and analyzed todetermine a response curve of the tissue that indicates how a signalcharacteristic changes in response to the one or more test signals.Examples of detected signal characteristics include but are not limitedto: energy, power, amplitude, frequency, energy at one or morefrequencies or range of frequencies, duration, temperature change,dispersion or acoustic radiation force. The treatment parameter isselected or controlled based on the response curve(s).

In one embodiment, a response curve is compared to find a match againstpredefined response curves having treatment parameters associatedtherewith and the treatment parameter(s) of the closest matchingresponse curve is selected.

In another embodiment, a treatment parameter is selected by analyzing acharacteristic of the response curve, such as a saturation point orslope and the treatment parameter(s) associated with the characteristicis selected.

In yet another embodiment, a treatment parameter is selected bycomparing the response curves to threshold values.

In one embodiment, the response curve is determined by comparing theenergy of the received signals created from the test signals in onefrequency range to the energy of the received signals in a secondfrequency range. This comparison is used to calculate K, which is theratio of the energy in the two frequency ranges. In one embodiment, theenergy in the harmonic content of the waveform is compared to the energyin the fundamental frequency. In another embodiment, the energy in asingle harmonic, such as the second harmonic, is compared to the energyat the fundamental frequency. In yet another embodiment, the energy inone group of frequencies is compared to the energy in another group offrequencies, of which one may contain the fundamental frequency. In yetanother embodiment, the phase difference for the harmonics can be usedto calculate K.

The ratio K may be found for a multitude of spatial positions from thetransducer. This may be accomplished through windowing of the receivedsignals from the tissue at a specific time and calculating the Fouriertransform. The response curve formed by the values of K as a function ofspatial location may be compared to a baseline response curve, and theexcitation signal may be adjusted to optimize the HIFU energy deliveredto the intended target volume.

In one particular embodiment, the disclosed technology relates to amethod and apparatus for selecting a power level for a high intensityfocused ultrasound (HIFU) signal to be delivered by a HIFU transducerthat operates by: transmitting a test signal having a fundamentalfrequency to a target volume; receiving ultrasound echoes from one ormore positions; determining an energy of the received echoes in a firstfrequency range and an energy of the echo signals in a second frequencyrange; comparing the energy of the received echoes in the firstfrequency range and the energy of the echo signals in the secondfrequency range; and based on the comparison, adjusting one or morecharacteristics of the HIFU signal to adjust the energy of the HIFUsignal delivered by the HIFU transducer.

In still a further embodiment, the method and apparatus operate suchthat the first frequency range does not include the fundamentalfrequency of the test signal and the second frequency range does includethe fundamental frequency of the test signal.

In still a further embodiment, the method and apparatus operate suchthat the first frequency range includes one or more harmonics of thefundamental frequency of the test signal.

In still a further embodiment, the method and apparatus operate suchthat the energy of the received echoes in the first frequency range andthe energy of the echoes in the second frequency range are compared bydetermining a ratio of an energy of the echoes in the first frequencyrange to an energy of the echoes in the second frequency range.

In yet another embodiment, the method and apparatus operate such thatthe delivered energy of the HIFU signal is adjusted by determining ifthe ratio at a selected position is less than a threshold, and if so,adjusting a characteristic of the HIFU signal to increase the deliveredenergy of the HIFU signal at the selected position.

In yet another embodiment, the method and apparatus operate so that thedelivered energy of the HIFU signal is adjusted by determining if theratio at a selected position is greater than a threshold, and if so,adjusting a characteristic of the HIFU signal to decrease the deliveredenergy of the HIFU signal at the selected position.

In yet another embodiment, the method and apparatus operate so that theenergy of the echoes in the first frequency range and the energy of theechoes in the second frequency range are compared by determining adifference in phase between the echoes in the first frequency range andthe second frequency range.

In yet another embodiment, the method and apparatus operate so that theadjustment of one or more characteristics of the HIFU signal is madebased on the magnitude of the difference in phase.

In another embodiment, the response curve of the signal characteristicrelates a dispersion of an echo signal to variations in test signalpower. The dispersion may be detected as an amount of speckle shifttoward the HIFU transducer. The one or more treatment parameters arecontrolled or selected based on the amount of speckle shift detected.

In another embodiment, the response curve of the signal characteristicrelates how the energy contained in a received signal at one harmonic orat the fundamental frequency of the test signals varies in response tovariations in test signal power.

In another embodiment, the response curve of the signal characteristicrelates how a speckle shift due to heating within the tissue changeswith changes in test signal power.

In one embodiment, a single test signal at each power level is used tomeasure the response of the signal characteristic. In anotherembodiment, two interrogations signals are used for each power leveltested. The interrogation signals have the same overall power, but are180 degrees out of phase. In this case, the signals received from tissuecreated by the two signals are added together to suppress thefundamental frequency and give a record of the harmonics generatedwithin tissue.

This summary is provided to introduce a selection of concepts in asimplified form that are further described below in the DetailedDescription. This summary is not intended to identify key features ofthe claimed subject matter, nor is it intended to be used as an aid indetermining the scope of the claimed subject matter.

DESCRIPTION OF THE DRAWINGS

The foregoing aspects and many of the attendant advantages of thedisclosed technology will become more readily appreciated as the samebecome better understood by reference to the following detaileddescription, when taken in conjunction with the accompanying drawings,wherein:

FIG. 1 illustrates a basic system for controlling the energy of adelivered HIFU signal, in accordance with an embodiment of the disclosedtechnology;

FIG. 2A shows a received echo as a function of time;

FIG. 2B shows a received echo as a function of distance;

FIG. 3 shows windowed sections of a received echo at three differentdistances;

FIG. 4 shows the frequency spectrum of a windowed echo (distance of 35mm) with the fundamental, 3rd and 5th harmonics identified;

FIG. 5 shows a surface plot of the power in decibels as a function offrequency and distance mapped to a grayscale;

FIG. 6 shows an expected K value curve as a function of distance ‘r’;

FIGS. 7A-7C show a surface plot of the power in decibels as a functionof frequency and depth taken at three different times, t0, t1 and t2;

FIG. 8 shows a graphical representation of K value matrices fordifferent distances and acquisition times;

FIG. 9 shows a graphical representation of the steps performed to obtainK value curves and change the energy/power of a delivered HIFU signal inaccordance with an embodiment of the disclosed technology;

FIGS. 10A-10C illustrate the differences between burst length, burstinterval, pulse length, and pulse rate interval of a pulsed HIFU signal;

FIG. 11 illustrates an embodiment of a HIFU treatment system in whichthe disclosed technology can be implemented;

FIGS. 12A and 12B illustrate different types of transducer probes thattransmit HIFU signals and receive echo signals from the patient;

FIGS. 13A and 13B illustrate different feedback control systems toadjust the energy of a delivered HIFU signal; and

FIG. 14 illustrates a system for adjusting the delivered energy of aHIFU signal in accordance with another embodiment of the disclosedtechnology;

FIG. 15 illustrates the amplitude versus depth of an echo signal createdin tissue as a result of a HIFU signal;

FIG. 16 is a graph of the energy in the echo signal at the fundamentalfrequency of the HIFU signal versus depth;

FIG. 17 is a graph of the energy in the echo signal at the secondharmonic of the HIFU signal versus depth;

FIG. 18 is a two dimensional plot of the energy in the echo signal atthe second harmonic of the HIFU signal versus depth and power level of aHIFU signal;

FIG. 19 is a plot of the energy in the echo signal at the secondharmonic of the HIFU signal versus the power level of a HIFU signal.

FIG. 20 is a plot of dispersion created in echo signals in response toHIFU signals transmitted at different power levels;

FIG. 21 is a plot of dispersion created in echo signals in response toHIFU signals transmitted at different power levels;

FIG. 22 is a flowchart of steps performed to select a power level forHIFU signals to be used to treat a tissue site in accordance with anembodiment of the disclosed technology; and

FIG. 23 illustrates a system for adjusting a focus point of a deliveredHIFU signal in accordance with another aspect of the disclosedtechnology.

DETAILED DESCRIPTION

Although the technology disclosed herein is described with respect toits currently preferred embodiments and the best mode known forpracticing the technology, the description is not to be construed aslimiting. The disclosure is directed to all new and non-obvious featuresand aspects of the disclosed embodiments either taken alone or incombination. As discussed above, the technology disclosed herein relatesto techniques for adjusting or selecting one or more treatmentparameters of a HIFU signal such as the energy of a HIFU signal and/orthe location at which the energy is delivered. For the purposes of thisapplication, the energy of a HIFU signal may be characterized by itspower, pressure or other related characteristic. Other treatmentparameters that can be controlled or selected include the treatmenttimes of the HIFU signals, pulse repetition frequency, pulse duration ofthe HIFU signals or other parameters that effect the amount or rate atwhich energy is deposited at a tissue treatment site.

As will be described in further detail below, the one or more treatmentparameters of the HIFU signals that are used to treat a tissue site arecontrolled or selected based on an analysis of how the signalcharacteristics of received signals vary in response to one or more testsignals. In a currently preferred embodiment, the test signals are oneor more HIFU signals. However, the test signals could be any type ofultrasound signal including non-focused or imaging ultrasound signals.The same transducer may be used to deliver both the therapeutic HIFUsignals and the test signals or different ultrasound transducers couldbe used.

In one embodiment, to select the value of a treatment parameter, anumber of test signals at different power levels are transmitted intothe tissue. The test signals may be transmitted to the same tissueregion as the target treatment site or the test signals may betransmitted into tissue into tissue that is nearby the target treatmentsite.

As the power level of the test signals increase, the transmitted testsignals become increasingly non-linear in the tissue in the focal zoneof the ultrasound transducer. The non-linearity creates a correspondingresponse curve of a signal characteristic that can be detected and usedto select the appropriate treatment parameter. In one embodiment, theresponse curve is analyzed for a power level of a test signal thatcauses the detected signal characteristic to saturate. The saturationpower level is used as a basis for selecting the treatment parameter.

The treatment parameter may be selected for each tissue site to betreated. Alternatively, the selected treatment parameter may be used totreat several different areas or cross-sections of the tissue site to betreated.

FIG. 1 shows a diagram of a system for selecting a treatment parametersuch as the energy of a HIFU signal for use in treating a tissue site inaccordance with an embodiment of the disclosed technology. The system 10includes a HIFU transducer 12 that delivers a HIFU signal to tissue 14and HIFU electronics 16 that excites the transducer 12. A voltage probe18 detects an electrical signal at the HIFU transducer 12. The systemfurther includes an oscilloscope or other data acquisition system 20. Inthis case, an excitation signal from the HIFU electronics 16 stimulatesthe HIFU transducer 12 such that a high energy ultrasound signal istransmitted to the intended target in tissue 14. The energy in the HIFUsignal is scattered, reflected, transmitted and absorbed as itpropagates within the tissue. The absorbed energy is converted to heatand causes the temperature of the tissue to rise. The amount of energyabsorbed depends on the pressure amplitude and frequency as well as thetissue characteristics. Typically, a HIFU device is designed such thatthe greatest pressure and absorption occur at the focal point of thedevice in the tissue. Energy of the signal that is not absorbed iseither transmitted to deeper tissues or reflected and scattered. In oneembodiment of the disclosed technology, it is the reflected andscattered energy (ultrasound echoes) that can be detected and analyzedfor harmonic distortion. Some of this scattered acoustic energy isdetected by the HIFU transducer 12 and converted into an electricalsignal. The electrical signal is sensed using the voltage probe 18 anddisplayed/acquired on the oscilloscope or other data acquisition system20.

FIG. 2A shows a representative signal captured at the data acquisitionsystem 20 with three regions identified, namely transmit, pulse-echosaturation, and pulse-echo signal. For this example, the focal depth is35 mm for the HIFU transducer. If it is assumed that acquisition startsimmediately when transmit begins, then the first detected signal willcontain mostly information from the transmit pulse (transmit region).After transmit ends, it is expected that some of the first few echoesmay cause clipping in the detection system (pulse-echo saturation). Theissues with pulse-echo saturation may be mitigated by properly designingthe detection circuit to ensure satisfactory dynamic range and bandwidth(e.g. time-gain control). After the initial large amplitude echoes havebeen received, the echoes from the tissue may be detected without anyadditional distortion added from the detection system (pulse-echosignal). Since in the embodiment shown, the HIFU transducer anddetection transducer are the same, the time axis also represents depththrough knowledge of the propagation velocity in the tissue as shown inFIG. 2B.

The energy of the echo signals as a function of frequency may becomputed at different depths or spatial locations. In one case, thereceived echo signal is multiplied by a windowing function centered at aspecific depth and the Fourier transform operator is applied. In theexample shown in FIG. 3, echo signals are isolated at depths centered at25, 35 and 45 mm with a rectangular function which is 5 mm in width. Itis expected that the window width and amplitude will be adjusted tooptimize the frequency representation of the echo signal. A Fouriertransform of the echo signals at each depth signal is calculated todetermine the energy of the echo signals as a function of frequency.FIG. 4 shows the frequency spectrum for the signal windowed at 35 mm. Inthis case, the fundamental frequency, 3^(rd) harmonic, and 5^(th)harmonic are identified. The even harmonics are typically not as easy todetect due to therapy transducer limitations. Although only three depthsare shown in FIG. 3, the window function can run along the entire lengthof the pulse-echo signal or vector. In this case, a matrix of data iscomputed such that one axis is depth and the other axis is frequency.FIG. 5 shows a three dimensional surface plot in grayscale of acontinuous analysis along the depth dimension. In this representation,the fundamental frequency of 1.1 MHz has been removed using a digitalfilter, which highlights the harmonics seen at 3.3 MHz and 5.5 MHz.

The Fourier transform determines the energy that occurs in a number offrequency bins. Therefore, the energy in a particular frequency bin maybe compared to the energy in other frequency bins or the energy overmultiple frequency bins may be summed and compared. For example,frequencies around the fundamental frequency (e.g. bandwidth) may be abetter representation of the power. EQUATIONS 1A and 1B show twodifferent cases for calculating a ratio K, of the energy as representedby the power at two different frequencies or in different frequencyranges.

As with many signal processing schemes, signal conditioning may berequired to detect and properly represent the energy of the echo signalsat the various frequencies. For example, the sensitivity of thedetection transducer or attenuation as a function of frequency and depthmay need to be introduced to fully appreciate differences in the energyat the various frequencies in tissue.

$\begin{matrix}{{K_{f\; 1f\; 0}(r)} = \frac{P\left( {f_{1},r} \right)}{P\left( {f_{0},r} \right)}} & \left( {1A} \right) \\{{K_{f\; 1f\; 0}(r)} = \frac{\sum\limits_{f = {f_{1} - {\Delta\; f}}}^{f_{1} + {\Delta\; f}}{P\left( {f,r} \right)}}{\sum\limits_{f = {f_{0} - {\Delta\; f}}}^{f_{0} + {\Delta\; f}}{P\left( {f,r} \right)}}} & \left( {1B} \right)\end{matrix}$

FIG. 5 shows that the K values can be calculated as a function ofspatial position or depth; therefore, K is a function of r or spatialdistance. It is important to note that the calculation may include onefrequency or multiple frequencies. For example, the K value mayrepresent the energy in the harmonics compared to the energy in thefundamental.

FIG. 6 shows an example of how the K values are expected to vary as afunction of depth. In this example, the energy around the fundamental iscompared to the energy in the harmonics. As can be seen, the ratio K hasa maximum at or adjacent the focal point of the HIFU signal and thendecreases with increasing distance away from the transducer.

As described, it is possible to map the energy ratio as a function offrequency and spatial location for an echo. If the excitation level atthe transducer is modified, then it is also possible to compare K valuesfor different HIFU transducer pressures. The echoes are also availableat different sampling intervals (pulse repetition interval). Forexample, if a pulse mode HIFU excitation is used, then the echo may bedetected and analyzed between the excitation signals. This allows the Kvalues to be compared for multiple excitation levels and/or multipletimes. FIGS. 7A-7C show multiple surface plots that have been acquiredfrom different echoes at times t0, t1 and t2. This may be due tovariation in excitation level or just processing between excitationtimes. The frequency spectrum at each spatial location is calculated,and then K is calculated.

FIG. 8 shows a representative format for storing K data in a computermemory. In one embodiment, the data is stored in a table 50 where oneaxis 52 is spatial location (depth) and another axis 54 is acquisitiontime. Each entry for a particular depth and time contains a matrix,e.g., 56, wherein the power ratio between two frequencies is calculatedand stored. In this representation, K_(f2f0) is the power ratio in thethird harmonic to the fundamental frequency. K_(f2f1) is the power ratioin the third harmonic to the second harmonic. Since K is just a ratio ofthe power in two frequencies, K_(f2f1) is simply the multiplicativeinverse of K_(f1f2). If it is necessary to compare the power in thefundamental to all harmonics, then essentially the column needs to besummed as set forth in EQUATION 2.K _(total)(r ₀ ,t ₀)=K _(f) ₂ _(f) ₀ (r ₀ ,t ₀)+K _(f) ₂ _(f) ₀ (r ₀ ,t₀)+K_(f) ₃ _(f) ₀ (r ₀ ,t ₀)+ . . . +K _(f) _(N) _(f) ₀ (r ₀ ,t ₀)  (2)

FIG. 8 also shows that the K values may be calculated at differentexcitation times t0, t1, t2, etc. By comparing the K values at thesetimes (note: the excitation may vary at these different times) betweeneach other or to a baseline, the approximate location of the focus maybe determined as well as an estimate of the energy of the HIFU signaldelivered to the tissue.

The values of K can be used to select a treatment parameter for the HIFUsignals to be used in treating a tissue site by analyzing the K curvedetermined for the tissue. As indicated above, the system transmits oneor more test signals into the patient and detects signals created by thetest signals. The ratio, K, of the energy detected in differentfrequency bands versus depth can be used to create a K curve. The Kcurve of the detected signals can be compared against known K curves forwhich treatment parameters have already been determined. For example,breast tissue may be associated with a K curve having a first set of oneor more treatment parameters. Fibroid tissue may be associated withanother K curve having different treatment parameters. In oneembodiment, a processor compares the K curve for the detected signalswith a library of K curves to determine the closest match and selectsthe treatment parameters associated for the closest match.

In another embodiment, one or more individual points on a K curve forthe detected signals can be compared with a predetermined baseline Kcurve. The value for the treatment parameter can be adjusted based onthe comparison. For example, if the characteristic curve formed by K asa function of spatial location for the detected signals showssignificantly higher ratios than the baseline curve, then the outputenergy (pressure) may be reduced. Similarly, if the characteristic curveformed by K as a function of spatial location for the detected signalsshows significantly lower ratios (or flatter) than the baseline curve,then the output energy may be increased.

It is also possible to show harmonic saturation (maximum value for theratio K) by graphing the K values as a function of the excitationamplitude for a particular depth. In this case, a number of test HIFUsignals are transmitted at different power levels and the K values forthe detected signals are computed. A curve or plot of the change in Kversus changes in HIFU power for a particular depth are computed. Thecurve or plot can then be compared against known plots having treatmentparameters associated with them. Alternatively, the K curve can becompared with a baseline K curve and the treatment parameters selected.

In one embodiment, one or more points on the K curve for the detectedsignals are used to select the treatment parameters. In one embodiment,the K curve can be searched for a HIFU power level that causes the valueof K to saturate. The treatment parameters of the HIFU signals used totreat a tissue sample can therefore be selected based on the HIFU powerwhich causes the K value to saturate. For example, if the HIFU powerthat causes the value of K to saturate is 1500 watts, then the treatmentparameters associated with a 1500 watt level can be used to treat thetissue. In some cases it may be useful to use the same power to treatthe tissue as the power that causes the value of K to saturate. In othercases, other power levels (greater or lessor) could be used.

In yet another embodiment, other characteristics of the K curve for thedetected signals can be used to select the treatment parameters. Forexample, the slope of the K curve can be compared with slopes of Kcurves having treatment parameters associated with them or the slope ofthe K curve for the detected signals can be compared with a baseline andthe treatment parameters adjusted accordingly.

If the excitation level is constant during the treatment, the energylevel of the harmonics and their location may suggest the amount ofheating occurring throughout the tissue. This would help determine alimit to the amount of energy delivered to the intended target.

It should be also noted that although the power spectrum has beencalculated at different depth and acquisition times, the phase may alsobe used to determine the amount of heating in tissue.

Since the K-value may be derived by the taking the Fourier transform ofthe echo signals, the power (energy per unit time) falling within eachfrequency bin as well as the phase is available for computation. Themagnitude and phase in a particular frequency bin may be expressed inthe following equation:H(f ₁)=A(f ₁)*e ^(−j2πφ(f) ¹ ⁾  (3)where A(f₁) is the amplitude of the signal at frequency f₁ (the power issimply the square of A) and φ(f₁) is the phase of the signal atfrequency f₁. Therefore, the phase difference between two frequency binsmay be computed by taking the ratio of Equation 3 with the magnitudenormalized to 1:

$\begin{matrix}{\in_{f_{1}f_{0}}{= \frac{{\mathbb{e}}^{{- j}\; 2{{\pi\varphi}{(f_{1})}}}}{{\mathbb{e}}^{- {{j2\pi\varphi}{(f_{0})}}}}}} & (4)\end{matrix}$Equation 4 may be rewritten asε_(f) ₁ _(f) ₀ =e ^(−j2π(φ(f) ¹ ^()−φ(f) ₀))  (5)The argument in Equation 5 is the phase difference between the twosignals. The phase difference as a function of depth at differentexcitation levels may also be used as a relative measure of energy indifferent frequencies or frequency bands, which in turn may be used todynamically control or select a treatment parameter of a HIFU signal.For example, the magnitude of the phrase difference can be compared to athreshold previously known to relate the phase difference to deliveredenergy in the tissue. One or more characteristics of the HIFU signal canthen be adjusted in accordance with the comparison.

FIG. 9 shows a summary of the basic steps to acquire the K values inaccordance with one embodiment of the disclosed technology. First, theHIFU transducer is excited with a single frequency (f_(o)) as shown ingraph 1. The HIFU signal may be a continuous wave (CW) or a pulsedsinusoid with a fundamental frequency f₀. In the case of CW, the pulserepetition interval is equal to the pulse length. As shown in graph 1,the HIFU excitation signal generated at the HIFU transducer probe has asignature spectrum where the energy of the frequency components that aredifferent from the fundamental frequency of the HIFU signal, such as theharmonics, f₁, f₂, f₃, etc., are negligible compared with the energy ofthe fundamental frequency f₀. The high pressures created from thetransmitted HIFU signal converts the energy at the fundamental toharmonics and in the tissue (graph 2). In particular, the energy of thesignal at frequencies that are different from the fundamental frequencyf₀ the HIFU signal (such as the frequency of one or more of theharmonics f₁, f₂, f₃, etc.) changes in comparison to the energy of thesignal at the fundamental frequency f₀ as shown in graph 2. K values arecalculated by combining the energies at these various frequencies asshown in graphs 3 a, b and c. For example, the energy in one or more ofthe harmonics may be compared to the fundamental frequency. The energyin several lower order harmonics and the fundamental may be compared tothat of the high frequency harmonics. Alternatively, the energy in thefundamental may only be compared to that of the higher order harmonics.These graphs by no means exhaust the possibilities of combining andcomparing the energies at the various frequencies. As will beappreciated by those skilled in the art, the value of K may varydepending on the range of frequencies or particular harmonics used incomputing the numerator and denominator.

Graph 4 shows that the K values may be graphed as a function ofposition. The ratio K may vary with the depth in the tissue as well aswith different levels of transmit excitations. In one embodiment, theratio K is expected to be a non-linear curve that increases withincreasing depth in the tissue, but tends to reach a maximum (orsaturate) at approximately the depth of the focal point of the HIFUsignal. If K values are calculated after each transmit pulse (graph 5),then multiple K value curves may be generated as shown in graph 4.

Graph 5 shows that the frequency of the transmit pulses may occur at thepulse repetition interval. FIGS. 10A-10C illustrate a pulse length and apulse repetition interval in a burst. Many pulse lengths make up aburst. Each burst has a defined burst length, and the time between thestart of each burst is the burst interval as shown in FIG. 10A. EachHIFU burst includes a number of HIFU pulses having a pulse length, wherethe time between the start of each pulse is the pulse rate interval asshown in FIG. 10B. The total time of the transmit excitation is thepulse length as shown in FIG. 10C. Each HIFU pulse is a sinusoidalwaveform having a fundamental frequency f₀.

Returning to FIG. 9, a first curve 70 in graph 4 illustrates the ratio Kfor a first delivered energy level of the HIFU signal and a second curve74 illustrates the ratio of K for a higher level of energy. By observingthe changes in the K values as a function of depth, time, or transmitexcitation, then a relative measure of the energy deposited spatiallymay be approximated.

The energy of the HIFU signal can be modified by increasing ordecreasing any of the burst length, the burst interval, the pulselength, the pulse rate interval, or other characteristics such as thepulse amplitude. In one embodiment, the HIFU treatment systemautomatically varies the acoustic output energy or power as a functionof both the characteristic K curve relative to the baselinecharacteristic curve and whether the device is within an acceptablerange for the values of K. An acceptable range for K may have an upperlimit for pre-focal and focal values of K, based on safety levels. Othertreatment parameters such as treatment time or pulse repetitionfrequency of the HIFU signals can be selected in a similar manner.

FIGS. 1 through 10 illustrate an embodiment of the disclosed technologystarting with a simple block diagram. As one trained in the art willappreciate, there are other versions of this technology that generatesimilar benefits. FIG. 11 is another block diagram of a HIFU treatmentsystem for implementing the technology disclosed herein. In theembodiment, a HIFU controller 110 delivers electronic driving signals toan external or internal transducer probe 116 that in turn converts thedriving signals into acoustic HIFU signals. In FIG. 11, the HIFUtransducer probe 116 is shown in a wand-like apparatus. It is importantto note that the HIFU transducer many have a plurality of elements inmultiple dimensions that are mechanically or electronically steered toproperly direct the ultrasound signal to the intended target. Forexample, the HIFU signals may be directed to a focal zone that is aimedat a target volume 118 through electronic or mechanical means. Thetarget volume 118 may include all or a portion of a fibroid in a uterus120. The HIFU signals create corresponding echo signals from tissue thatare intercepted by the acoustic propagation. In most cases, the HIFUsignal energy is concentrated on an axis that is located between thetransducer probe 116 and the focal zone.

The echo signals are received by the transducer probe 116, convertedinto an electronic form and supplied to the HIFU controller 110. Thedetection of the echo signals may take place in the HIFU transducer oranother specially designed device contained within the transducer probe116. Furthermore, the detection device may be in a separate holder notcontained within the transducer probe 116.

As previously described, the K values from the echo signals arecalculated (FIG. 9), analyzed, and used to control or select one or moretreatment parameters. An ultrasound processor 124 that is connected toor incorporated within the HIFU controller 110 analyzes the receivedecho signals and computes the K values. Based on the analysis, one ormore treatment parameters or characteristics of the HIFU excitationsignal (e.g., peak power, average power, pulse duration, pulserepetition interval, etc.) are automatically or semi-automaticallyadjusted by the ultrasound processor 124. In some cases, the operatormay be alerted via an audible, visible, or tactile alert 130 to manuallyadjust one of the device parameters through a control on the device(e.g., main console control 112, applicator, footswitch). A safetymechanism to ensure treatment does not continue without proper feedbacksignals may also be employed. In some instances, the system may alsoinclude ultrasound imaging capabilities that produce images of thetissue on a video display 132. The images may be obtained with aseparate or integrated imaging ultrasound transducer. These images maybe used to confirm proper adjustment of the HIFU excitationcharacteristics.

To estimate how much of the incident HIFU energy is being absorbed bythe tissue at various positions at or adjacent to the focal point of theHIFU signal, the value of the ratio K is determined from the echosignals received from a given point in the tissue. In one embodiment,the ratio is compared to a desired value of K that was determined fromprior testing. The value of the ratio K for the detected signals cantherefore be used as a feedback signal to adjust one or morecharacteristics of the HIFU signal to affect absorption and hence HIFUeffects on tissue at a given point. Detection of saturation (acousticshock waves) or the slope of the increase in the K value as a functionof the transmit excitation may also be used as feedback mechanisms toadjust one or more characteristics of the HIFU signal rather thandepending on prior testing.

In one embodiment, if the determined value of K for detected signals isbelow a threshold value for a particular position in the patient, then asignal characteristic such as the amplitude, peak or average power, dutycycle, pulse repetition rate, or other characteristic of the deliveredHIFU signals can be electronically or manually increased to increase theratio K at that position. Conversely, if the determined value of K isabove a threshold, then one or more of the amplitude, power, duty cycle,pulse repetition rate, or other characteristic of the HIFU signal can bedecreased to decrease the value of K. Different threshold values of Kmay be used to analyze echo signals received from within the targetvolume and outside that target volume in the body.

FIGS. 12A and 12B illustrate two possible applicator configurations thatdeliver HIFU signals to a target volume and detect echo signals at thefundamental frequency of the HIFU signal and at harmonics or otherfrequencies. In the example shown in FIG. 12A, a HIFU transducer probe200 delivers one or more HIFU signals to a target volume. The HIFUtransducer probe may have a fixed or variable focal point. Echo signalsare received by a separate receiving transducer 220. The receivingtransducer 220 has a bandwidth that is sufficient to detect echo signalsover a range of frequencies that may include the fundamental frequencyof the HIFU signals produced by the transducer probe 200 and itsharmonics. The receiving transducer 220 may be an ultrasound imagingtransducer, a non-imaging transducer such as a polyvinylidene fluoride(PVDF) transducer, a fiber optic hydrophone or other form of hydrophone.The receiving transducer 220 may be positioned to detect echo signalsreflected back from the focal point. Alternatively the receivingtransducer 220 may be positioned to detect signals that are transmittedthrough the focal point and away from the HIFU transducer.

In the example shown in FIG. 12B, a combination HIFU transmitting andreceiving transducer probe 230 includes HIFU transmitting elements 232that produce the HIFU signals and an array of higher bandwidth receivingelements 234 that are used to detect echo signals over a range offrequencies that may include the fundamental frequency of the HIFUsignals and may also include one or more harmonics. The transducer inFIG. 12B may utilize a PVDF or other type of sensor.

FIGS. 13A and 13B illustrate two different feedback mechanisms to adjusta treatment parameter of a HIFU signal to be delivered. In FIG. 13A, acontrol signal 239 from the HIFU controller 110 is applied to a waveformgenerator 240 to produce a waveform of the HIFU signals that will beapplied to the patient. A control signal 249 is also applied to thewaveform generator 240 by a signal processing unit 248 such as aprogrammable microprocessor or special purpose microprocessor within theultrasound processor 224 that correlates the transmission and receipt ofHIFU signals. Alternatively, the signal processing unit 248 may be astand-alone device. The signals from the waveform generator 240 aresupplied to a pulser 242 that increases the voltage of the signals tothe level required by a HIFU transducer 244 to produce ultrasoundacoustic signals. Echo signals are received by the HIFU transducer 244where they are converted back into an electronic form for supply to areceiver 246. From the receiver 246, the echo signals are supplied tothe signal processing unit 248 that analyzes the echo signals inaccordance with the control to determine the ratio K described above.The signal processing unit 248 produces the control signal signals 249that are fed back to the waveform generator 240 to electronically changeone or more characteristics of the HIFU signals in order to change theenergy or other characteristic of the HIFU signals delivered to thepatient such that the detected ratio K falls within a desired range.

The feedback mechanism shown in FIG. 13B is similar to that shown inFIG. 13A except that a separate transducer 245 is used to detect theecho or other (e.g. transmitted) signals from the patient. For example,the transducer 245 may be a high bandwidth single element transducersuch as a transducer with a PVDF material, or it may be an imagingtransducer. Echo or non-reflected signals received by the transducer 245are supplied to the receiver 246 and the signal processing unit 248 thatdetermines the value of the ratio K and what, if any, characteristics ofthe HIFU signals should be electronically adjusted to control the energyor other characteristic of the HIFU signals delivered to the patient.

In yet another embodiment, the system includes an integrated or separateultrasound imaging system that produces ultrasound images such as B-modeimages of the tissue. The value of the ratio K is determined for variouspoints in the body and is color coded or otherwise made visuallydistinct. The visually distinguished K values in the tissue can then becombined with a B-mode or other type of ultrasound image. In oneembodiment, the color coded K values 134 are overlaid onto a B-modeimage on the display 132 as shown in FIG. 11. By viewing the variouslevels of K, the physician can see where the higher frequency componentsof the HIFU signals are being created. The physician can then adjust theposition of the HIFU transducer probe so that the HIFU signals are beingdelivered into the desired area. In addition or alternatively, thephysician can see if one or more characteristics of the HIFU signalsshould be adjusted to change the amount of energy delivered to thepatient.

In another embodiment, the system may calculate the center of mass, alsocalled a centroid, for use in the physician's on-screen display, byanalyzing the harmonics received by the system. This reduces the overallclutter in the on-screen display.

In another embodiment, the system records the value of the inputs thatprovide the K ratio value. This allows the system to detect acorrelation between pulses in order to build a successive picture oftrends in feedback characteristics. This may, for example, provideinformation valuable in determining whether cavitation or other tissuecharacteristics have occurred. The system may also make use of pulseinversion in order to create a data set of K ratio values over time foruse in feedback analysis that eliminates the fundamental.

FIG. 14 illustrates another embodiment of the disclosed technology whereinstead of calculating the value K by Fourier transform, a number offilters 300 detect the energy of the echo signals in various frequencyranges. The filters can be digital (e.g., FIR or IIR) or analog (e.g.,bandpass, notch, etc.). The value K can then be determined digitally orwith an analog circuit 302.

Another possible embodiment of this technique is to use basebanddetection along with low pass filtering to determine the energy in adetected signal at the fundamental as well as at one or more of theharmonics. The acquired rf vector at a particular power setting isdetected and multiplied by sine and cosine waves at the fundamental orharmonic frequencies to obtain baseband data:B _(n)(t)=x(t)*exp(−j2πnft)

where f is either the fundamental frequency, n the order of the harmonic(e.g. n is one for the fundamental and 2 for the second harmonic), t isthe time vector, x(t) is the original rf waveform, and B, is thebaseband detected signal.

After mixing with the sine and cosine waves, the signal is low passfiltered to eliminate energy from other harmonics. The bandwidth of thelow pass filter is driven by the bandwidth of the original excitation.After the low pass filter, the signal may be decimated to a lowersampling frequency. The baseband detected signal is associated with aspecific transmit power and is a function of depth.

In addition or as an alterative to controlling treatment parametersbased on the ratio of the energy in different frequency regions, othercharacteristics of the detected signals can also be used to select orcontrol the treatment parameters.

FIG. 15 shows an original ultrasound echo obtained from an in-vivoporcine subject in which a HIFU signal was targeted at 107 mm. FIGS. 16and 17 show the baseband detected signals for the fundamental and secondharmonic of the echo signal respectively. As more signals are acquiredat different power levels, a filter may be applied over the ensemble ofdetected signals to reduce noise artifacts. Furthermore, additionalfiltering in depth and power dimension may be applied due to theexpected transitions. FIG. 18 shows a 2D image of the second harmonicenergy as a function of depth and excitation power. To select atreatment parameter such as the desired transmit power, a search regionmay be defined around the expected focus. The size of the search regionwill vary depending on the depth-of-field of the transducer andpotential variances in propagation velocity.

As will be described below, the response of a signal characteristic tochanges in the power of a transmitted HIFU signal is used to select oneor more treatment parameters of HIFU signals that will be used to treata tissue site. FIG. 19 illustrates a response curve showing how theenergy of a received signal at the second harmonic of the HIFU testsignals varies with changes in HIFU power for a tissue area near thefocal point of the transducer. Depending on how many test signals areused, the response curve would be created from a series of discrete datapoints obtained for different transmit powers that are thenmathematically smoothed.

In the example shown, the response curve shown in FIG. 19 is computedfrom received echo signals at the second harmonic of the HIFU transmitfrequency. However it will be appreciated that the signal detected couldbe a signal that passes through the treatment site or could be computedfor another harmonic or range of frequencies or combination ofharmonics. In general, the response curve will be computed for a signalcharacteristic that exhibits a measurable change with changes intransmitted HIFU power.

In one embodiment, to select the one or more treatment parameters to beused in treating a tissue site, the response curve for the tissue isdetermined using a number of test signals transmitted at different powerlevels. The response curve may be compared to previously known responsecurves having treatment parameters associated with them. The treatmentparameters associated with the previously known response curve that bestmatches the response curve for the tissue site in question can be usedto treat the tissue site. Alternatively, one or more points on theresponse curve for the tissue can by analyzed to select the one or moretreatment parameters.

In one embodiment, the response curves can be analyzed to determine asaturation point, slope or other characteristic such as the shape of thecurve. FIG. 19 shows a saturation point for the second harmonic signalnear the focus with a power saturation value of approximately 1500 W.The treatment parameters associated with a 1500 watt saturation pointcan therefore be used to treat the tissue.

To automate the determination of the saturation levels in the focalregion the response curve is analyzed with a suitably programmedprocessor or computer. In one embodiment, the goal is to identify thepower which exhibits the highest level of scattered energy and thusenergy absorption. Ideally regions with significant amounts of harmonicenergy would be used to maximize signal-to-noise ratio. For example, thepeaks throughout the search region may be selected rather than eachsample.

In one embodiment, a look-up-table (LUT) of expected response curves isused to determine the saturation values around the focus. This LUT mayconsist of response curves predicted theoretically with differentcharacteristics such as attenuation and isentropic non-linearityparameter B/A. Statistical techniques such as correlation are used tocompare the theoretical curves to the detected response curve. In thiscase, it is possible to obtain the saturation power as well as theeffective characteristics of the tissue path such as attenuation thatcan be used to determine the length of treatment time to treat thetissue site.

In another embodiment, the processor or computer is programmed todetermine the first and second derivatives of the determined responsecurve. Next, regions that are concave down with both positive andnegative slopes on either side are identified and considered thesaturation value.

In yet another embodiment, the expected first and second derivatives areused to code the waveform at a particular depth. Rather than look for aplace that has a slope of zero and is concave down, the processor orcomputer is programmed to use other characteristics of the expectedcurve predicted by theory or other controlled experiments to increasethe confidence that the correct saturation value was chosen. A code isassigned to the expected waveform and the code of the experimental datais determined based on the sign of the first and second derivative. Forexample, a code of zero is assigned to a slope of zero, a code of one toa negative slope and code of two to a positive slope. In this case, eachpoint analyzed on the response curve could have one of nine possiblecodes (e.g. 00, 01, 02, 10, 11 etc.). The code is modified only if thereis a change between the value of the first and second derivativesbetween samples, which further compresses the data. A correlation valuemay be determined between the coded expected value and the codedexperimental value to increase the reliability of the algorithm. If thecorrelation is not above a certain value, then the saturation cannot bedetermined.

In some embodiments, the curve with the lowest saturation value is usedas the prediction. Another method is to average the results through thesearch region and utilize this for treatment. Ideally, the process fordetermining the saturation value occurs in real-time such thatexorbitant power values are not used.

This idea may be extended to lesions at different depths. In this case,interrogations at different lesion locations are completed. Theestimated saturation levels are compared. This allows for the possiblecalculation of the effective attenuation in the treatment region.

In yet another alternative embodiment of the disclosed technology, theresponse curve for the detected signals that is analyzed to determinethe treatment parameters is related to the temperature change at thefocal zone. In this case, HIFU test signals are transmitted and a changein temperature is determined based a detected speckle shift of areflected signal (echo) or transmitted signal. Speckle shifts aredetermined for a number of HIFU signals transmitted at different powerlevels in order to generate the response curve. Preferably the test HIFUsignals are sufficiently short so that the tissue in the focal zone doesnot undergo sustained heating prior to treatment or between testsignals. The response curve is analyzed by comparing againstpredetermined response curves or by determining some characteristic suchas its saturation point, whereby the speckle shift no longer increasesor decreases with increases in delivered HIFU signal power. Once theresponse curve has been analyzed either by comparison to previouslydetermined response curves or by analyzing selected points on theresponse curve, the treatment parameters can be selected.

In yet another alternative embodiment, a response curve related to thedispersion of the waveform transmitted into the tissue is used tocontrol or select the treatment parameter for the HIFU signals to beused to treat the target tissue site.

Dispersion occurs in acoustic waves and is noted by a slight velocitydifference of the wavefront that is a function of frequency although thegroup velocity may remain constant. In high intensity acoustics,dispersion in the wave pulse naturally occurs in regions of highcompression due to the production of harmonics. The high pressure andnon-linearities of tissue eventually lead to acoustic shock at thehighest compressional pressures. The production of harmonics anddispersion are less likely to occur in low pressure pulses. As thepressure is increased, the amount of dispersion increases sinceharmonics are more easily generated. This dispersion is detected as aphase shift in the waveform as the amplitude of the excitation movesfrom low pressure to high pressure. The dispersion is seen as movementof the rf signal toward the transducer and is localized by the area ofhigh pressure. This is unique when compared to other effects such asacoustic radiation force (ARF) and apparent phase shifts due totemperature changes. In both of these cases, the expectation is thephase shift is away from the transducer. Furthermore, velocity changesdue to temperature are an integrative effect in tissue. In other words,where the local temperature has increased, the shift will appear at thatpoint as well as for every point behind the thermal increase.

FIG. 20 shows the changes that occur in the pressure pulse at the focusat increasing transmit pressures 400, 402, 404, 406. Each pulse has beennormalized for purposes of illustration. In this case, the fiber opticpressure hydrophone (FOPH) is receiving the transmitted pulse at thefocus (in this case 64 mm). The high compressional pressure produces theshock that appears between 2.9 usec and 3.1 usec in FIG. 20. As thepressure is increased, the shock front is produced prior to the focuswhich yields to the detected dispersion at the focus. FIG. 20 capturesthe movement of the compression peak from a low excitation level (400)to a high excitation level (406). In this case, the movement isapproximately 0.1 usec. FIG. 21 shows the received echo from a pointtarget at the focus at the same transmit power levels 400, 402, 404,406. The PVDF sensor shows dispersion occurring for negative as well aspositive pressures. This is due to the PVDF sensor impulse response.When a wide bandwidth wavefront such as that shown in FIG. 21 impingesthe PVDF sensor surface, the sensor will mechanically vibrate equally incompression and rarefaction.

The resulting phase shifts shown in FIGS. 20 and 21 are detected as aspatial shift in an ultrasound image. This spatial shift may be detectedon rf as well as detected data. Furthermore, the detected phase shiftmay be used to localize areas of high pressure. Therefore, it ispossible to create a pressure map of the body based on dispersion.

Dispersion may be detected as a slight shift in the image or speckletoward the HIFU transducer as test signals of successively higher powerare applied to the tissue. This is illustrated in FIGS. 20 and 21 inwhich the higher level DAQ settings correspond to higher power levelsand the time to receive the wavefront corresponds to its positionrelative to the transducer.

As the power level is increased, there is a corresponding increase inproduction of harmonics at the focal region—which in turn reduces thetime to receive the signal scattered from the focal region, due todispersion. This reduced time can be perceived as a spatial shift in theultrasound image towards the transducer, assuming the signals aredisplayed graphically.

As shown in the attached flowchart of FIG. 22, to determine a treatmentparameter such as a power level setting for HIFU to be delivered to atissue treatment site, a therapy transducer is briefly excited at anumber of test power level settings. At each such setting, abackscattered ultrasound signal is detected with the same transducerthat delivers the signals or with a different transducer. Thebackscattered signals are stored until each of the possible power levelsare tested or until an optimal power level is determined.

After delivering the test signals with the different power levelsettings, the speckle shift associated with adjacent power levelsettings is determined. A response curve showing the change in thespeckle shift versus changes in HIFU power is created with a programmedprocessor or computer. The response curve is analyzed and used to selectone or more treatment parameters. For example, a programmed processorcan analyze the response curve to determine a power level at which thespeckle shift saturates i.e. doesn't change with further increases inpower or the amount of speckle shift decreases with further increasedpower. In one embodiment, the treatment parameters are selected based onthe power level of the HIFU that causes saturation. Other signalscharacteristics such as the slope of the response curve can be used toselect the treatment parameters. In yet another alternative embodiment,the response curve can be compared with predefined response curveshaving treatment parameters associated with them. The treatmentparameters associated with the response curve that best matches thedetermined response curve can be used to treat the tissue.

In one embodiment, treatment of each location within an intendedtreatment volume may be immediately preceded by determination of thetreatment parameters for that location. In another embodiment, thetreatment parameters may be determined at a variety of locations withinan intended treatment volume prior to commencing treatment of any suchlocation. The treatment parameters for each location are then stored ina memory or other computer readable media. Once treatment begins, theselected treatment parameters are recalled for each such location andused to treat that location. In yet another embodiment, the treatmentparameters selected for one location can be used to treat an entirevolume of tissue.

To maximize the accuracy and consistency of this method for selectingtreatment parameters, the successive test HIFU signals should be spacedtogether closely in time so as to minimize any spatial shifts that mightoccur due to tissue motion (e.g. due to breathing or other patientmotion).

In addition, the test signals should be applied in a manner whichminimizes local heating of tissue, so as to avoid shifts that mightoccur due to changes in local sound velocity.

In yet another embodiment, the energy in a received signal at harmonicsof the fundamental frequency of the HIFU signal can be estimated bymeasuring the energy at the fundamental frequency. This technique allowsa more narrow band detection system to be used.

If a HIFU signal is delivered to the tissue at power P₁ (that isselected to be low enough not to create energy at the harmonics in thetissue) and at a distance r, the HIFU signal will produces a signal withenergy at the fundamental frequency of the HIFU signal that is definedby a function:Xf(P1,r)  (6)

If the tissue behaved linearly, then the energy at the fundamental of asignal created from a HIFU signal that is transmitted at a higher powerlevel P₂, should be related to the different power level by thefunction:

$\begin{matrix}{{{Xf}\left( {{P\; 2},r} \right)} = {\frac{P\; 2}{P\; 1}{{Xf}\left( {{P\; 1},r} \right)}}} & (7)\end{matrix}$

However the tissue generally does not respond linearly to higher powerlevels of HIFU signals. Therefore the measured energy at the fundamentalfrequency of a signal that is created in response to a higher power HIFUsignal will differ from the prediction. The difference is related to theenergy that is being converted into the energy at the harmonics.

To estimate the energy at the harmonics, the energy of a received signalat the fundamental frequency of the HIFU signal that is delivered at apower level P₂ is determined. The difference between the energy measuredand the energy predicted is calculated. according to the function:

$\begin{matrix}{{Xh} = {{\frac{P\; 2}{P\; 1}*{{Xf}\left( {{P\; 1},r} \right)}} - {{Xf}\left( {{P\; 2},r} \right)}}} & (8)\end{matrix}$

where Xh is the energy at the harmonics. The ratio of the energy in theharmonics to the energy at the fundamental frequency of the HIFU signalsis therefore given by the function:

$\begin{matrix}{\frac{{Xh}\left( {{P\; 2},r} \right)}{{Xf}\left( {{P\; 2},r} \right)} = {\frac{\frac{P\; 2}{P\; 1}{{Xf}\left( {{P\; 1},r} \right)}}{{Xf}\left( {{P\; 2},r} \right)} - 1}} & (9)\end{matrix}$

A response curve can therefore be created that relates the energy of theharmonics to increases in the energy of the HIFU signals delivered. Theresponse curve can be analyzed by a programmed processor or computer andused to select the treatment parameters either by comparison againstpredetermined response curves having treatment parameters associatedtherewith or by analyzing characteristics of the response curve andselecting treatment parameters associated with the characteristics.

In yet another embodiment, the “focal gain” i.e. the increased energyabsorption caused by the energy level of the harmonics that is createdin the tissue can be estimated by comparing the energy of the signalscreated from HIFU signals at different powers. If the tissue werelinear, then the following relationship should hold for different HIFUpower levels.

$\begin{matrix}{\frac{X\left( {{P\; 2},r} \right)}{\frac{P\; 2}{P\; 1}{X\left( {{P\; 1},r} \right)}} = 1} & (10)\end{matrix}$

However as the power level increases, more energy is transferred to theharmonics and the ratio should become less than one with a drop in thedetected energy at the HIFU power level that causes a saturation ifmeasured with a narrow band receiver or a gain in the detected energy atthe energy level that causes saturation if measured with a wide bandreceiver. Therefore, a response curve can be determined that relates theratio of detected energy to predicted energy at several different HIFUpower levels. The response curve can then be analyzed or compared toother response curves in order to select one or more treatmentparameters.

As will be appreciated by those skilled in the art, the deposition ofenergy at a treatment site is effected by the tissue's “alpha” valuethat is related to attenuation as well as its “B/A” value that isrelated to the tissue's isentropic non-linearity parameter B/A.

The alpha value for the tissue treatment site can be estimated bymeasuring the energy of a signal created in response to a test HIFUsignal at a fixed power. The transducer can then be moved away from thetreatment site and the space filled with a medium of known attenuatione.g. water. A second test HIFU signal is then applied to the tissue andthe energy detected. A response curve in this example therefore relatesthe difference in energies detected and the distance that the transducerwas moved. From the estimated attenuation of the tissue, a treatmentregimen (power and treatment duration or other treatment parameter) canbe selected based on predetermined clinical data performed on tissuetypes with similar alpha values. The alpha value for the tissue can bedetermined by comparing response curves for different spatial locationsin the tissue.

The B/A value for a tissue site to be treated can be estimated based oncomparison of the tissue's response curve with response curves computedfor tissue types with known B/A values.

As indicated above, the treatment parameters such as power level, pulseduration, pulse repetition frequency etc. are selected based on ananalysis of the response of the tissue to be treated to a HIFU pulse.The particular values for these treatment parameters will be based onclinical data and stored in a manner that can be indexed based on ananalysis of the response curve for the treatment site. The parameterdata is typically stored in a computer readable media, hard drive, CDROM, solid state memory etc, that is accessed by a local or remotecomputer. When needed, the recalled treatment parameters are applied tothe HIFU control hardware so that the tissue can be treated.

In addition or as an alternative to selecting or adjusting the energy ofthe delivered HIFU signals, the disclosed technology can be used toredirect the focus point of the delivered signals. In the embodimentshown in FIG. 23, a therapy transducer 350 delivers a number of testsignals to a tissue site at the same or different power levels. Adetection transducer 352 receives the corresponding echo or othersignals, which are provided to a processor (not shown) that computesresponse curves, such as the K values described above or response curvesbased on other signal characteristics, at a number of positions in thetissue. In the example shown, the K values have a maximum value at apoint 360 which is offset from an intended focus point 362 of the testsignals. By comparing the location of the maximum K value to theintended focus point, the processor can determine if the focus point ismisaligned. By computing the offset between the location of the maximumK value at 360 and the intended focus point at 362, a difference vectorcan be determined and the difference vector supplied to a beam formingequation used by a waveform generator to cause the therapy transducer350 to redirect the focus point of the HIFU process towards the desiredfocus point 362. Alternatively, the difference vector can be supplied toa mechanical mechanism (not shown) that physically reorients the focusof the HIFU transducer. The process can continue by continuing tomeasure K values from the received echo signals and computing thelocation of the maximum K value and comparing it to the desired focuspoint until such time as the maximum K value is within a predetermineddistance of the desired focus point.

If the response curves are created based on other signalcharacteristics, the focus can be redirected based on the responsecurves determined for each of the spatial locations.

Although illustrative embodiments of the disclosed technology have beenillustrated and described, it will be appreciated that various changescan be made therein without departing from the scope of the technology.For example, the response curves may also be produced for a change inacoustic radiation force (ARF) that relates movement of the tissue tochanges in power of the test signals. In addition, the disclosedtechnology is not limited to the delivery of HIFU signals to the patientbut can be applied to the delivery of any waveform such as non-focusedultrasound to a non-linear medium such as tissue. Therefore, the scopeof the technology is to be determined solely by the following claims andequivalents thereof.

The invention claimed is:
 1. A method of operating a high intensityfocused ultrasound (HIFU) system to treat a target treatment site, themethod comprising: transmitting two or more test signals into a tissuesite, wherein two or more of the test signals are transmitted atdifferent power levels at a fundamental frequency; detecting signalsfrom an area of the tissue site, wherein the detected signals resultfrom transmission of the two or more test signals into the tissue site;determining one or more response curves for the tissue site thatindicate how a signal characteristic of the detected signals changes inresponse to the different power levels of the two or more test signals,wherein at least one of the response curves relates how energy in thetest signals transfers from the fundamental frequency to one or moreharmonics of the fundamental frequency with the different power levelsof the test signals by comparing the energy of the detected signals atthe fundamental frequency to the energy of the detected signals at theone or more harmonics using a computed ratio of the energy of thedetected signals at the fundamental frequency to the energy of thedetected signals at the one or more harmonics; using at least one of thedetermined response curves to select a treatment parameter of HIFUsignals that will be used to treat the target treatment site; andapplying HIFU signals with the selected treatment parameter to thetarget treatment site with the HIFU system.
 2. The method of claim 1,wherein at least one of the response curves relates how an energy levelof a detected signal at a harmonic of the fundamental frequency varieswith the different power levels of the test signals.
 3. The method ofclaim 1, wherein the two or more test signals include test signalstransmitted in at least two different frequency ranges, and wherein atleast one of the response curves relates how an energy level of adetected signal in the different frequency ranges varies with depth inthe tissue site.
 4. The method of claim 1, wherein at least one of theresponse curves relates how an energy level of a detected signal at thefundamental frequency varies with the different power levels.
 5. Themethod of claim 1, wherein the two or more test signals include testsignals transmitted in at least two different frequency ranges, andwherein at least one of the response curves relates how an energy levelof a detected signal at the different frequency ranges varies with thedifferent power levels.
 6. The method of claim 1, wherein the two ormore test signals include test signals transmitted in at least twodifferent frequency ranges, and wherein at least one of the responsecurves relates how an energy level of a detected signal in a singlerange of frequencies varies with the different power levels.
 7. Themethod of claim 1, wherein at least one of the response curves is usedto select the treatment parameter by determining a closest match of theresponse curve to a number of predetermined response curves each havinga treatment parameter associated therewith, and selecting the treatmentparameter associated with the predetermined response curve that bestmatches the at least one response curve.
 8. The method of claim 1,wherein at least one of the response curves is used to select thetreatment parameter by determining a characteristic of the responsecurve and selecting a treatment parameter associated with thecharacteristic.
 9. The method of claim 8, wherein the characteristic ofthe response curve is a saturation point of the response curve.
 10. Themethod of claim 8, wherein the characteristic of the response curve is ashape of the response curve.
 11. The method of claim 1, wherein at leastone of the response curves relates how a dispersion of a detected signalvaries with the different power levels.
 12. The method of claim 1,wherein at least one of the response curves relates how a speckle shiftrelated to changes in temperature at the target treatment site varieswith the different power levels.
 13. The method of claim 1, wherein morethan one test signal is transmitted at a power level, and wherein eachtest signal transmitted at the same power level includes a pair of testsignals having opposite phases.
 14. A high intensity focused ultrasound(HIFU) system to treat tissue at a target treatment site, the systemcomprising: an ultrasound transducer that is configured to deliver twoor more test signals to a tissue site, wherein at least two of the testsignals are transmitted at different power levels at a fundamentalfrequency; a controller that is configured to control the ultrasoundtransducer to deliver the two or more test signals to the tissue site; areceiver that is configured to detect signals from the tissue site,wherein the detected signals result from transmission of the two or moretest signals into the tissue site; a processor programmed to analyze thedetected signals to determine one or more response curves for the tissuesite that indicate how a signal characteristic of the detected signalschanges in response to the different power levels of the two or moretest signals, wherein at least one of the response curves relates howenergy in the test signals transfers from the fundamental frequency toone or more harmonics of the fundamental frequency with the differentpower levels of the test signals by comparing the energy of the detectedsignals at the fundamental frequency to the energy of the detectedsignals at the one or more harmonics using a computed ratio of theenergy of the detected signals at the fundamental frequency to theenergy of the detected signals at the one or more harmonics, wherein theultrasound transducer is further configured, under control of thecontroller, to deliver HIFU signals to the target treatment site with aselectable treatment parameter, and wherein the processor is programmedto select the treatment parameter for the HIFU signals to be used intreating the target treatment site based on at least one of thedetermined response curves.
 15. The system of claim 14, wherein at leastone of the response curves relates how an energy level of a detectedsignal at a harmonic of the fundamental frequency varies with thedifferent power levels of the test signals.
 16. The system of claim 14,wherein the two or more test signals include test signals transmitted inat least two different frequency ranges, and wherein at least one of theresponse curves relates how an energy level of a detected signal in thedifferent frequency ranges varies with depth in the tissue site.
 17. Thesystem of claim 14, wherein at least one of the response curves relateshow an energy level of a detected signal at the fundamental frequencyvaries with the different power levels.
 18. The system of claim 14,wherein the two or more test signals include test signals transmitted inat least two different frequency ranges, and wherein at least one of theresponse curves relates how an energy level of a detected signal at thedifferent frequency ranges varies with the different power levels. 19.The system of claim 14, wherein the processor is programmed to selectthe treatment parameter by determining a closest match of at least oneof the response curves to a number of predetermined response curves eachhaving a treatment parameter associated therewith, and selecting thetreatment parameter associated with the predetermined response curvethat best matches the at least one response curve.
 20. The system ofclaim 14, wherein processor is programmed to select the treatmentparameter by determining a characteristic of at least one of theresponse curves and selecting a treatment parameter associated with thecharacteristic.
 21. The system of claim 20, wherein the characteristicof the at least one response curve is a saturation point of the responsecurve.
 22. The system of claim 20, wherein the characteristic of the atleast one response curve is a shape of the response curve.
 23. Thesystem of claim 14, wherein at least one of the response curves relateshow a dispersion of the detected signal varies with the different powerlevels.
 24. The system of claim 14, wherein the ultrasound transducer isconfigured to deliver more than one test signal at a power level, andwherein each test signal transmitted at the same power level includes apair of test signals having opposite phases.
 25. The system of claim 14,wherein the receiver is a HIFU transducer.
 26. The system of claim 14,wherein the receiver is an ultrasound imaging transducer.
 27. The systemof claim 14, wherein the receiver is a polyvinylidene fluoride (PVDF)transducer.
 28. The system of claim 14, wherein the receiver is ahydrophone.
 29. The system of claim 14, wherein the processor isprogrammed to produce a signal to adjust the treatment parameter. 30.The system of claim 29, wherein the signal is perceptible by a human tomanually adjust the treatment parameter.
 31. The system of claim 29,wherein the signal is used in a feedback loop of the HIFU system todynamically adjust the treatment parameter.
 32. The system of claim 14,wherein the processor is programmed to select the treatment parameter bycomparing characteristics of at least one of the response curves tothreshold values.
 33. A system for applying HIFU signals to a subject,the system comprising: a HIFU controller configured to produceelectronic HIFU driving signals having one or more adjustablecharacteristics that affect an energy of a delivered HIFU signal; a HIFUtransducer configured to receive the electronic HIFU driving signals,produce acoustic HIFU signals at a fundamental frequency, and apply theacoustic HIFU signals to tissue of a subject; a receiving transducerconfigured to detect echo signals from the tissue of the subject; aprocessor configured to receive the detected echo signals and compare anenergy of the echo signals in a first frequency range to an energy ofthe echo signals in a second frequency range at a number of locations inthe tissue; and a display for displaying an image of the tissue alongwith an image representative of the comparison at one or more locationsin the tissue, wherein the processor is configured to compare the energyof the echo signals in the first frequency range to the energy of theecho signals in the second frequency range by computing a ratio of theenergy of the echo signals in the first frequency range to the energy ofthe echo signals in the second frequency range, wherein the ratio of theenergy of the echo signals relates how energy in the HIFU signalstransfers from the fundamental frequency to one or more harmonics of thefundamental frequency, and wherein the processor is configured to usethe computed ratio of the energy of the echo signals to select a powerlevel of the acoustic HIFU signals which adjusts the energy delivered bythe HIFU signals in the tissue of the subject.
 34. The system of claim33, wherein the processor is further configured to quantify the ratio ina visually or audibly perceptible form.
 35. The system of claim 34,wherein the visually perceptible form is a color code.
 36. A method ofadjusting a focal location of a HIFU transducer, the method comprising:transmitting two or more test signals at different power levels intotissue at an intended focal location, wherein two or more of the testsignals are transmitted at a selected frequency; receiving echo signalsat a number of spatial locations in the tissue, wherein the echo signalsresult from transmission of the two or more test signals into thetissue; determining one or more response curves for the tissue at eachof the spatial locations that indicate how a signal characteristic ofthe echo signals changes with changes in the power level of the two ormore test signals, wherein at least one of the response curves relateshow energy in the test signals transfers from the selected frequency toone or more harmonics of the selected frequency with the different powerlevels of the test signals, and wherein the one or more response curvescompare energy in the echo signals resulting from a test signaltransmitted at a first power level to energy in the echo signalsresulting from a test signal transmitted at a second power level bycomputing a ratio of the energy of the echo signals at the first powerlevel to the energy of the echo signals at the second power level;analyzing the one or more response curves to determine an estimate of anactual focal location; and adjusting the intended focal location basedon the estimate of the actual focal location.
 37. The method of claim36, wherein said adjusting the intended focal location is performedsuccessively until a minimum required difference between the estimatedactual focal location and intended focal location is achieved.
 38. Themethod of claim 36, wherein said adjusting the intended focal locationis performed successively until a maximum number of iterations isachieved.
 39. A high intensity focused ultrasound (HIFU) system to treattissue at a target treatment site, the system comprising: an ultrasoundtransducer that is configured to deliver two or more test signals at afocal location, wherein the two or more test signals are transmitted atdifferent power levels; a controller that is operates to adjust thefocal location of the ultrasound transducer; a receiver that isconfigured to detect echo signals at a number of spatial locations,wherein the detected echo signals result from transmission of the two ormore test signals into the spatial locations; and a processor that isprogrammed to analyze the detected echo signals to determine one or moreresponse curves that indicate how a signal characteristic of thedetected echo signals changes in response to the two or more testsignals transmitted at the different power levels into the spatiallocations, wherein at least one of the response curves relates howenergy in the test signals transfers from a selected frequency to one ormore harmonics of the selected frequency with the different power levelsof the test signals, and wherein the one or more response curves compareenergy in the echo signals resulting from a test signal transmitted at afirst power level to energy in the echo signals resulting from a testsignal transmitted at a second power level by computing a ratio of theenergy in the echo signals at the first power level to the energy of theecho signals at the second power level, and wherein the processor isprogrammed to cause the controller to adjust the focal location of theultrasound transducer based on at least one of the determined responsecurves.
 40. A method of adjusting a focal location of an ultrasoundtransducer, comprising: transmitting an ultrasound signal into tissue atan intended focal location with a first transducer; receiving echosignals from the tissue with a second transducer; determining the energyof the received echo signals in a first frequency range and a secondfrequency range; comparing the energy of the received echo signals inthe first frequency range to the energy of the received echo signals inthe second frequency range by computing a ratio of the energy of thereceived echo signals in the first frequency range to the energy of thereceived echo signals in the second frequency range, wherein the ratioof the energy of the received echo signals relates how energy in theultrasound signal at a frequency in the second frequency range transfersto one or more harmonic frequencies in the first frequency range; andusing the computed ratio to adjust the focal location of the firsttransducer.
 41. A high intensity focused ultrasound (HIFU) system totreat tissue at a target treatment site, comprising: an ultrasoundtransducer that is configured to deliver a test signal to a tissue siteat an intended focal location; a controller that is operates to adjustthe intended focal location of the ultrasound transducer; a receiverthat is configured to receive echo signals at a number of spatiallocations in the tissue site; and a processor programmed to compare theenergy of the received echo signals in a first frequency range to theenergy of the received echo signals in a second frequency range for thespatial locations by computing a ratio of the energy of the receivedecho signals in the first frequency range to the energy of the receivedecho signals in the second frequency range, wherein the ratio of theenergy of the received echo signals relates how energy in the testsignal at a frequency in the second frequency range transfers to one ormore harmonic frequencies in the first frequency range, and further usethe computed ratio to adjust the focal location of the ultrasoundtransducer.
 42. The high intensity focused ultrasound (HIFU) system ofclaim 41, wherein the processor determines a location of a maximumdifference in the energy in the first and second frequency ranges as anestimate of an actual focal location, and causes the controller toadjust the intended focal location based on the estimate of the actualfocal location.
 43. The method of claim 40, further comprising:determining a location of a maximum difference in the energy in thefirst and second frequency ranges as an estimate of an actual focallocation; and adjusting the intended focal location based on theestimate of the actual focal location.